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      5-Hydroxymethylcytosine as a potential epigenetic biomarker in papillary thyroid carcinoma

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          Abstract

          DNA methylation at the 5 position of cytosine (5-mC) is an epigenetic hallmark that is critical in various biological and pathological processes such as DNA methylation regulation, and initiation and development of cancers. 5-mC can be oxidized to 5-hydroxymethylcytosine (5-hmC) by the ten-eleven translocation family of DNA hydroxylases. Accumulating evidence has reported that loss of 5-hmC is associated with cancer development. However, its level in papillary thyroid carcinoma (PTC) remains unclear. The present study reports that the loss of 5-hmC is an epigenetic mark of PTCs, associated with their malignant biological behavior, providing diagnostic and predictive advantages over DNA hypomethylation (5-mC), an acknowledged epigenetic alteration in cancer. In addition, the 5-hmC staining levels were decreased in cases of micro-carcinoma with lymph node metastasis, which suggests that 5-hmC expression levels could be used as valuable biomarkers for predicting malignant potential and assist in the selection of therapeutic strategies in PTC; therefore, 5-hmC has the potential to provide a more precise direction for PTC therapy.

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          TET enzymes, TDG and the dynamics of DNA demethylation.

          Rahul M. Kohli, Yi Zhang (2013)
          DNA methylation has a profound impact on genome stability, transcription and development. Although enzymes that catalyse DNA methylation have been well characterized, those that are involved in methyl group removal have remained elusive, until recently. The transformative discovery that ten-eleven translocation (TET) family enzymes can oxidize 5-methylcytosine has greatly advanced our understanding of DNA demethylation. 5-Hydroxymethylcytosine is a key nexus in demethylation that can either be passively depleted through DNA replication or actively reverted to cytosine through iterative oxidation and thymine DNA glycosylase (TDG)-mediated base excision repair. Methylation, oxidation and repair now offer a model for a complete cycle of dynamic cytosine modification, with mounting evidence for its significance in the biological processes known to involve active demethylation.
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            Role of TET enzymes in DNA methylation, development, and cancer

            Kasper Rasmussen, Kristian Helin (2016)
            Ten eleven translocation (TET) genes, and especially TET2, are frequently mutated in various cancers, but how the TET proteins contribute to the onset and maintenance of these malignancies is largely unknown. In this review, Rasmussen and Helin highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. The pattern of DNA methylation at cytosine bases in the genome is tightly linked to gene expression, and DNA methylation abnormalities are often observed in diseases. The ten eleven translocation (TET) enzymes oxidize 5-methylcytosines (5mCs) and promote locus-specific reversal of DNA methylation. TET genes, and especially TET2 , are frequently mutated in various cancers, but how the TET proteins contribute to prevent the onset and maintenance of these malignancies is largely unknown. Here, we highlight recent advances in understanding the physiological function of the TET proteins and their role in regulating DNA methylation and transcription. In addition, we discuss some of the key outstanding questions in the field.
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              An observational trial for papillary thyroid microcarcinoma in Japanese patients.

              Yasuhiro Ito, Akira Miyauchi, Hiroyuki Inoue … (2010)
              The recent development and spread of ultrasonography and ultrasonography-guided fine needle aspiration biopsy (FNAB) has facilitated the detection of small papillary microcarcinomas of the thyroid measuring 1 cm or less (PMC). The marked difference in prevalence between clinical thyroid carcinoma and PMC detected on mass screening prompted us to observe PMC unless the lesion shows unfavorable features, such as location adjacent to the trachea or on the dorsal surface of the thyroid possibly invading the recurrent laryngeal nerve, clinically apparent nodal metastasis, or high-grade malignancy on FNAB findings. In the present study we report comparison of the outcomes of 340 patients with PMC who underwent observation and the prognosis of 1,055 patients who underwent immediate surgery without observation. Between 1993 and 2004, 340 patients underwent observation and 1,055 underwent surgical treatment without observation. These 1,395 patients were enrolled in the present study. Observation periods ranged from 18 to 187 months (average 74 months). The proportions of patients whose PMC showed enlargement by 3 mm or more were 6.4 and 15.9% on 5-year and 10-year follow-up, respectively. Novel nodal metastasis was detected in 1.4% at 5 years and 3.4% at 10 years. There were no factors related to patient background or clinical features linked to either tumor enlargement or the novel appearance of nodal metastasis. After observation 109 of the 340 patients underwent surgical treatment for various reasons, and none of those patients showed carcinoma recurrence. In patients who underwent immediate surgical treatment, clinically apparent lateral node metastasis (N1b) and male gender were recognized as independent prognostic factors of disease-free survival. Papillary microcarcinomas that are not associated with unfavorable features can be candidates for observation regardless of patient background and clinical features. If there are subsequent signs of progression, such as tumor enlargement and novel nodal metastasis, it would not be too late to perform surgical treatment. Even though the primary tumor is small, careful surgical treatment including therapeutic modified neck dissection is necessary for N1b PMC patients.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncol Lett
                Journal ID (iso-abbrev): Oncol Lett
                Journal ID (publisher-id): OL
                Title: Oncology Letters
                Publisher: D.A. Spandidos
                ISSN (Print): 1792-1074
                ISSN (Electronic): 1792-1082
                Publication date (Print): September 2019
                Publication date (Electronic): 27 June 2019
                Publication date PMC-release: 27 June 2019
                Volume: 18
                Issue: 3
                Pages: 2304-2309
                Affiliations
                [1 ]Department of Ultrasound, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116044, P.R. China
                [2 ]Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116044, P.R. China
                [3 ]Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116044, P.R. China
                Author notes
                Correspondence to: Dr Ying Che or Dr Lina Wang, Department of Ultrasound, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, Liaoning 116044, P.R. China, E-mail: yche1964@ 123456163.com , E-mail: 510664072@ 123456qq.com
                [*]

                Contributed equally

                Article
                Publisher ID: OL-0-0-10531
                DOI: 10.3892/ol.2019.10531
                PMC ID: 6676597
                PubMed ID: 31452729
                SO-VID: 2002fa15-00f1-4ce5-9c71-5212247d49b8
                Copyright © Copyright: © Tong et al.
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                Date received : 01 August 2018
                Date accepted : 22 May 2019
                Categories
                Subject: Articles

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 5-hydoxymethylcytosine,biological marker,papillary thyroid carcinoma,epigenetics
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: 5-hydoxymethylcytosine, biological marker, papillary thyroid carcinoma, epigenetics

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